Synthesis and biological evaluation of C-4 substituted phenoxazine-bearing hydroxamic acids with potent class II histone deacetylase inhibitory activities

Jung Chun Chu, Hui Ju Tseng, Sung Bau Lee, Kai Cheng Hsu, Ling Wei Hsin, Ru Hao Liang, Tony Eight Lin, Nain Chu Gao, Liang Chieh Chen, Wan Hsun Lu, Andrew H.J. Wang, Wei Jan Huang

研究成果: 雜誌貢獻文章同行評審

摘要

Class II histone deacetylases (HDACs) are considered as potential targets to treat Alzheimer’s disease (AD). Previously, C-3 substituted phenothiazine-containing compounds with class II HDAC-inhibiting activities was found to promote neurite outgrowth. This study replaced phenothiazine moiety with phenoxazine that contains many C-3 and C-4 substituents. Some resulting compounds bearing the C-4 substituent on a phenoxazine ring displayed potent class II HDAC inhibitory activities. Structure-activity relationship (SAR) of these compounds that inhibited HDAC isoenzymes was disclosed. Molecular modelling analysis demonstrates that the potent activities of C-4 substituted compounds probably arise from π-π stacked interactions between these compounds and class IIa HDAC enzymes. One of these, compound 7d exhibited the most potent class II HDAC inhibition (IC50= 3–870 nM). Notably, it protected neuron cells from H2O2-induced neuron damage at sub-μM concentrations, but with no significant cytotoxicity. These findings show that compound 7d is a lead compound for further development of anti-neurodegenerative agents.
原文英語
文章編號2212326
期刊Journal of Enzyme Inhibition and Medicinal Chemistry
38
發行號1
DOIs
出版狀態已發佈 - 2023

ASJC Scopus subject areas

  • 藥理
  • 藥物發現

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